The proposed research will clearly focus on the following hypothesis: Rat hepatocyte cultures are a sensitive model with which to study the influence of inhalation anesthetics and adjuvant drugs on local anesthetic metabolism, thereby providing the first direct information on changes in intrinsic clearance and in oxidative, hydrolytic and conjugative pathways of liver enzymes, and how these pathways are altered by aging. This will be accomplished by studying the kinetics of metabolism for bupivacaine using rat primary hepatocyte cultures in terms of Km and Vmax for the parent drug and primary metabolites, and the rates and distribution of products as a function of age. The extent of stereoselective enzymatic changes with aging using D-bupivaciane and L-bupivacaine as model substrates will be examined. Drug interactions between bupivacaine and clinically relavent drugs will be studied using propranolol and cimetidine as model compounds. Changes in these interactions associated with aging will be determined to clarify the importance of these interactions in terms of the practice of clinical anesthesia. The influence of general anesthetics (nitrous oxide, halothane, enflurane and isoflurane) on local anesthetic metabolism will be studied. The changes in kinetics of metabolism for halothane, enflurane and isoflurane using rat primary hepatocyte cultures in terms of Km, Vmax and distribution of products as a function of aging and exposure to isoniazid or phenobarbitol will be studied. The effect of oxygen tension on these variables will be studied as a function of aging. Anesthesiologists often select a regional over a general anesthetic technique in the interest of efficacy and safety for the patient. Many patients for whom regional anesthesia is the primary technique, also require general anesthesia supplementation during the operative period. Is such mixing of anesthetic techniques safe for all patients, in particular, the elderly? The measurement of Km and Vmax, as well as pathways and rates of product formation in both control cultures and in cultures exposed to inhalation anesthetics will provide direct information on changes in intrinsic or metabolic clearance. The results of this research will provide the first scientific basis on which an anesthesiologist can make drug combination and dosage decisions affecting elderly, potentially high risk patients.